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Evidence continues to mount that dietary components are important determinants of cancer risk and tumor behavior Although these linkages are fascinating, numerous inconsistencies are also evident in the literature. Although multifactorial, these discrepancies likely reflect variation in the ability of food constituents to reach and/or modify critical molecular targets. Genetic polymorphisms can alter the response to dietary components (nutrigenetic effect) by influencing the absorption, metabolism, or site of action. Like-wise, variation in DNA methylation patterns and other epigenomic events that influence overall gene expression can influence the biological response to food components and vice versa. Fluctuations in the ability of food components to increase or depress gene expression (nutritional transcriptomic effect) may also account for some of the inconsistencies in the response to foods. Functional proteomic studies that capture all of the proteins produced by a species and link them to physiological significance within the cell will be fundamental to understanding the relationship between dietary interventions, proteome changes, and cancer Although a bioactive food component may influence a number of key molecular events that are involved with cancer prevention, to do so it must achieve an effective concentration within the target site, be in the correct metabolic form, and bring about a change in one or more small molecular weight signals in the cellular milleau (metabolomic effects). Fundamental to assessing and evaluating the significance of the interrelationships among bioactive food components with nutrigenetics, nutritional epigenomics, nutritional transcriptomics, proteomics, and metabolomics is knowledge about the appropriate tissue/cell or surrogate to evaluate and validated biomarkers that reflect changes in each. As the era of molecular nutrition grows, a greater understanding about the role of foods and their components on cancer risk and tumor behavior will surely unfold. Such information will be critical in the development of effective preemptive approaches to reduce the cancer burden. [ABSTRACT FROM AUTHOR]

Dietary nutrients can influence cancer risk by inhibiting or enhancing carcinogenesis through diverse mechanisms of action. The identification and elucidation of their sites of action have been a focus of nutrition and cancer research for more than four decades. Transforming nutrition and cancer research from a predominantly observational to a molecular approach offers exciting opportunities for truly identifying those who will and will not benefit from dietary intervention strategies. The emerging field of nutritional genomics, defined here as the study of any genetic or epigenetic interaction with a nutrient, will be key to this evolution. Unraveling which genetic upregulation or downregulation leads to subsequent phenotype changes will not be easy. There is evidence that genetic polymorphisms can influence the dynamics between nutrients and molecular targets and, thus, contribute to variation in response among individuals. Because many molecular targets will likely be identified, it may be necessary to credential nutrients, that is, to determine which specific nutrient-related genetic and epigenetic changes bring about phenotypic changes, to establish which interactions are the most important and under what circumstances. Vitamin D, calcium, folate, selenium, genistein, and resveratrol are highlighted, because they represent specific classes of nutrients and illustrate the need to credential various nutrients to understand their physiological significance in cancer prevention. As the science of nutrition unfolds, a clearer understanding will emerge about how nutrients can modulate cancer risk through molecular interactions and how foods might be changed by agronomic approaches and/or biotechnology. Undeniably, embracing new genomic technologies offers exciting opportunities for advances in the broad area of nutrition, especially those related to cancer prevention. [ABSTRACT FROM AUTHOR]

Discoveries about molecular targets for nutrients will unquestionably provide important clues into how best to optimize nutrition for an individual. The 'Credentialing' of nutrients in terms of their influence on genetic and epigenetic events that bring about a desired phenotypic change is surely within the future of nutrition science. [ABSTRACT FROM AUTHOR]

Knowledge gaps persist about the efficacy of cancer prevention strategies based on dietary food components. Adaptations to nutrient supply are executed through tuning of multiple protein networks that include transcription factors, histones, modifying enzymes, translation factors, membrane and nuclear receptors, and secreted proteins. However, the simultaneous quantitative and qualitative measurement of all proteins that regulate cancer processes is not practical using traditional protein methodologies. Proteomics offers an attractive opportunity to fill this knowledge gap and unravel the effects of dietary components on protein networks that impinge on cancer. The articles presented in this supplement are from talks proffered in the "Nutrition Proteomics and Cancer Prevention" session at the American Institute for Cancer Research Annual Research Conference on Food, Nutrition, Physical Activity and Cancer held in Washington, DC on October 21 and 22, 2010. Recent advances in MS technologies suggest that studies in nutrition and cancer prevention may benefit from the adoption of proteomic tools to elucidate the impact on biological processes that govern the transition from normal to malignant phenotype; to identify protein changes that determine both positive and negative responses to food components; to assess how protein networks mediate dose-, time-, and tissue-dependent responses to food components; and, finally, for predicting responders and nonresponders. However, both the limited accessibility to proteomic technologies and research funding appear to be hampering the routine adoption of proteomic tools in nutrition and cancer prevention research. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.J.F., S.G.D., A.J.R. and K.E.D are minor shareholders of Summit Therapeutics plc., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

An important characteristic of cancer is that the disease can overcome the surveillance of the immune system. A possible explanation for this resistance arises from the ability of tumor cells to block the tumoricidal activity of host immune cells such as natural killer (NK) cells by inducing the localized accumulation of regulatory T (Treg) cells. Evidence exists that components in commonly consumed foods including vitamins A, D, and E, water-soluble constituents of mushrooms, polyphenolics in fruits and vegetables, and n-3 fatty acids in fish oil can modulate NK cell activities, Treg cell properties, and the interactions between those two cell types. Thus, it is extremely important for cancer prevention to understand the involvement of dietary components with the early stage dynamics of interactions among these immune cells. This review addresses the potential significance of diet in supporting the function of NK cells, Treg cells, and the balance between those two cell types, which ultimately results in decreased cancer risk., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

The Allium genus includes garlic, onions, shallots, leeks, and chives. These vegetables are popular in cuisines worldwide and are valued for their potential medicinal properties. Epidemiologic studies, while limited in their abilities to assess Allium consumption, indicate some associations of Allium vegetable consumption with decreased risk of cancer, particularly cancers of the gastrointestinal tract. Limited intervention studies have been conducted to support these associations. The majority of supportive evidence on Allium vegetables cancer-preventive effects comes from mechanistic studies. These studies highlight potential mechanisms of individual sulfur-containing compounds and of various preparations and extracts of these vegetables, including decreased bioactivation of carcinogens, antimicrobial activities, and redox modification. Allium vegetables and their components have effects at each stage of carcinogenesis and affect many biologic processes that modify cancer risk. This review discusses the cancer-preventive effects of Allium vegetables, particularly garlic and onions, and their bioactive sulfur compounds and highlights research gaps., (©2015 American Association for Cancer Research.)

The Mushroom Council convened the Mushrooms and Health Summit in Washington, DC, on 9-10 September 2013. The proceedings are synthesized in this article. Although mushrooms have long been regarded as health-promoting foods, research specific to their role in a healthful diet and in health promotion has advanced in the past decade. The earliest mushroom cultivation was documented in China, which remains among the top global mushroom producers, along with the United States, Italy, The Netherlands, and Poland. Although considered a vegetable in dietary advice, mushrooms are fungi, set apart by vitamin B-12 in very low quantity but in the same form found in meat, ergosterol converted with UV light to vitamin D2, and conjugated linoleic acid. Mushrooms are a rare source of ergothioneine as well as selenium, fiber, and several other vitamins and minerals. Some preclinical and clinical studies suggest impacts of mushrooms on cognition, weight management, oral health, and cancer risk. Preliminary evidence suggests that mushrooms may support healthy immune and inflammatory responses through interaction with the gut microbiota, enhancing development of adaptive immunity, and improved immune cell functionality. In addition to imparting direct nutritional and health benefits, analysis of U.S. food intake survey data reveals that mushrooms are associated with higher dietary quality. Also, early sensory research suggests that mushrooms blended with meats and lower sodium dishes are well liked and may help to reduce intakes of red meat and salt without compromising taste. As research progresses on the specific health effects of mushrooms, there is a need for effective communication efforts to leverage mushrooms to improve overall dietary quality., (© 2014 American Society for Nutrition.)

The development of nutrition and health guidelines and policies requires reliable scientific information. Unfortunately, theoretical considerations and empirical evidence indicate that a large percentage of science-based claims rely on studies that fail to replicate. The session "Strategies to Optimize the Impact of Nutrition Surveys and Epidemiological Studies" focused on the elements of design, interpretation, and communication of nutritional surveys and epidemiological studies to enhance and encourage the production of reliable, objective evidence for use in developing dietary guidance for the public. The speakers called for more transparency of research, raw data, consistent data-staging techniques, and improved data analysis. New approaches to collecting data are urgently needed to increase the credibility and utility of findings from nutrition epidemiological studies. Such studies are critical for furthering our knowledge and understanding of the effects of diet on health.

Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells and thereby promote recruitment of monocytes. Given the inhibitory effect of broccoli-derived compounds indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) on androgen-dependent pathways, we also reasoned that I3C and DIM could modulate the effect of androgen on CCL2-mediated pathways. Dihydrotestosterone was found to induce a time-dependent (0-72 hours) and concentration-dependent (0-1 nmol/L) increase in CCL2 mRNA levels in androgen-responsive human prostate cancer cells (LNCaP). This increase in CCL2 mRNA corresponded with increased secretion of CCL2 protein. The effect of dihydrotestosterone was mediated through an androgen receptor (AR)-dependent pathway as small inhibitor RNA against AR negated the induction of CCL2. Although dihydrotestosterone also induced TWIST1 mRNA, an epithelial-mesenchymal transition-related factor, and purported inducer of CCL2, blocking its expression with small inhibitor RNA did not inhibit dihydrotestosterone induction of CCL2 mRNA. Moreover, conditioned media from androgen-treated cells promoted human monocyte THP-1 cell migration and this effect was blocked by antibody against CCL-2. Both I3C and DIM inhibited promotional effects of dihydrotestosterone on CCL2 and migration. These results show that androgen may regulate CCL2 and promote inflammatory microenvironment in prostate tumors and that this process can be blocked by broccoli-derived compounds.

Allyl isothiocyanate (AITC) is a dietary component with possible anticancer effects, though much information about AITC and cancer has been obtained from cell studies. To investigate the effect of AITC on DNA integrity in vivo, a crossover study was conducted. Adults (n=46) consumed AITC, AITC-rich vegetables [mustard and cabbage (M/C)] or a control treatment with a controlled diet for 10 days each. On day 11, volunteers provided blood and urine before and after consuming treatments. Volunteers were characterized for genotype for GSTM1 and GSTT1 (glutathione S-transferases) and XPD (DNA repair). DNA integrity in peripheral blood mononuclear cells was assessed by single-cell gel electrophoresis. Urine was analyzed for 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and creatinine. Ten-day intake of neither AITC nor M/C resulted in statistically significant differences in DNA strand breaks [least squares mean (LSmean) % DNA in tail±S.E.M.: 4.8±0.6 for control, 5.7±0.7 for AITC, 5.3±0.6 for M/C] or urinary 8-oxodG (LSmean μg 8-oxodG/g creatinine±S.E.M.: 2.95±0.09 for control, 2.88±0.09 for AITC, 3.06±0.09 for M/C). Both AITC and M/C increased DNA strand breaks 3 h postconsumption (LSmean % DNA in tail±S.E.M.: 3.2±0.7 for control, 8.3±1.7 for AITC, 8.0±1.7 for M/C), and this difference disappeared at 6 h (4.2±0.9 for control, 5.7±1.2 for AITC, 5.5±1.2 for M/C). Genotypes for GSTM1, GSTT1 and XPD were not associated with treatment effects. In summary, DNA damage appeared to be induced in the short term by AITC and AITC-rich products, but that damage disappeared quickly, and neither AITC nor AITC-rich products affected DNA base excision repair., (Published by Elsevier Inc.)

The discovery of multiple selenoproteins has raised tantalizing questions about their role in maintaining normal cellular function. Unfortunately, many of these remain inadequately investigated. While they have a role in maintaining redox balance, other functions are becoming increasingly recognized. As the roles of these selenoproteins are further characterized, a better understanding of the true physiological significance of this trace element will arise. This knowledge will be essential in defining optimum intakes to achieve cellular homeostasis in order to optimize health, including a reduction in cancer, for diverse populations. Human variation in the response to selenium likely reflects significant interactions between the type and amounts of selenium consumed with the genome and a host of environmental factors including the totality of the diet, as discussed in this review.

Cancer stem cells often have phenotypic and functional characteristics similar to normal stem cells including the properties of self-renewal and differentiation. Recent findings suggest that uncontrolled self-renewal may explain cancer relapses and may represent a critical target for cancer prevention. It is conceivable that the loss of regulatory molecules resulting from inappropriate consumption of specific foods and their constituents may foster the aberrant self-renewal of cancer stem cells. In fact, increasing evidence points to the network delivering signals for self-renewal from extracellular compartments to the nucleus including changes in stem cell environments, inducible expression of microRNAs, hyperplastic nuclear chromatin structures, and the on/off of differentiation process as possible sites of action for bioactive food components. Diverse dietary constituents such as vitamins A and D, genistein, (-)-epigallocatechin-3-gallate (EGCG), sulforaphane, curcumin, piperine, theanine and choline have been shown to modify self-renewal properties of cancer stem cells. The ability of these bioactive food components to influence the balance between proliferative and quiescent cells by regulating critical feedback molecules in the network including dickkopf 1 (DKK-1), secreted frizzled-related protein 2 (sFRP2), B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and cyclin-dependent kinase 6 (CDK6) may account for their biological response. Overall, the response to food components does not appear to be tissue or organ specific, suggesting there may be common cellular mechanisms. Unquestionably, additional studies are needed to clarify the physiological role of these dietary components in preventing the resistance of tumor cells to traditional drugs and cancer recurrence., (Published by Elsevier Inc.)

Plant phytoalexins are a class of low molecular weight compounds that accumulate in response to biotic and abiotic elicitors such as pathogens, wounding, freezing, UV light, and exposure to agricultural chemicals. Phytoalexins have been identified in at least 75 plants including cruciferous vegetables, soybean, garlic, tomato, rice, beans, and potatoes suggesting plants may be a rich source of cancer-fighting compounds. Preclinical evidence suggests these compounds possess anticancer properties including an inhibition of microbial activity, cell proliferation, invasion and metastasis, hormonal stimulation, and stimulatory effects on expression of metabolizing enzymes. This review highlights the plausible molecular mechanisms through which phytoalexins regulate biological processes that can impinge cancer development. Targets of phytoalexins include signal transduction pathways, transcription factors, cell cycle checkpoints, intrinsic and extrinsic apoptotic pathways, cell invasion and matrix metalloproteinase, nuclear receptors, and the phase II detoxification pathway. Additional research should address physiological relevant dietary concentrations, combinations of phytoalexins and interactions with other dietary compounds, duration of exposure, and tissue specificity as variables that influence the effectiveness of phytoalexins on normal and cancerous processes.

A year-long intervention trial was conducted to characterise the responses of multiple biomarkers of Se status in healthy American adults to supplemental selenomethionine (SeMet) and to identify factors affecting those responses. A total of 261 men and women were randomised to four doses of Se (0, 50, 100 or 200 μg/d as L-SeMet) for 12 months. Responses of several biomarkers of Se status (plasma Se, serum selenoprotein P (SEPP1), plasma glutathione peroxidase activity (GPX3), buccal cell Se, urinary Se) were determined relative to genotype of four selenoproteins (GPX1, GPX3, SEPP1, selenoprotein 15), dietary Se intake and parameters of single-carbon metabolism. Results showed that supplemental SeMet did not affect GPX3 activity or SEPP1 concentration, but produced significant, dose-dependent increases in the Se contents of plasma, urine and buccal cells, each of which plateaued by 9-12 months and was linearly related to effective Se dose (μg/d per kg0·75). The increase in urinary Se excretion was greater for women than men, and for individuals of the GPX1 679 T/T genotype than for those of the GPX1 679 C/C genotype. It is concluded that the most responsive Se-biomarkers in this non-deficient cohort were those related to body Se pools: plasma, buccal cell and urinary Se concentrations. Changes in plasma Se resulted from increases in its non-specific component and were affected by both sex and GPX1 genotype. In a cohort of relatively high Se status, the Se intake (as SeMet) required to support plasma Se concentration at a target level (Se(pl-target)) is: Se(in) = [(Se(pl - target) - Se(pl))/(18.2ng d kg⁰.⁷⁵/ml per mu g)] .

In the present studies, we utilized prostate cancer cell culture models to elucidate the mechanisms of action of broccoli-derived phytochemicals 3,3'-diindolylmethane (DIM) and indole-3-carbinol (I3C). We found DIM and I3C at 1-5 µM inhibited androgen and estrogen-mediated pathways and induced xenobiotic metabolism pathway. By contrast, DIM and I3C induced cyclin inhibitors, indicators of stress/DNA damage, only at ≥25 µM. We also demonstrated that an inhibitory effect of DIM and I3C on cell growth involves inhibition of insulin-like growth factor-1 receptor expression. More importantly, we showed that differences in efficacies and mechanisms existed between DIM and I3C. These included differences in effective concentrations, a differential effect on androgen receptor binding, and a differential effect on xenobiotic metabolic pathway through aryl hydrocarbon receptor-dependent and -independent mechanism. Furthermore we determined that several other diet-derived cancer protective compounds, similar to DIM and I3C, exhibited pleiotrophic effects on signaling pathways that included proliferation, cell cycle, and nuclear receptors-mediated pathways. However, the efficacies and mechanisms of these compounds vary. We also showed that some cellular pathways are not likely to be affected by DIM or I3C when circulating concentration of orally ingested DIM or I3C is considered. Based on our results, a model for cancer protective effects of DIM and I3C was proposed., (Copyright © 2011 Wiley Periodicals, Inc.)

Mounting evidence continues to point to dietary habits as a modifier of cancer risk and tumor behavior; although it is clear that considerable variability occurs across studies. While genetic public health messages can be developed, the use of mean values may result in underexposure to some essential and nonessential food components, yet precipitate overexposure to nutrients. Undeniably, inconsistencies in the literature may reflect variation in timing of exposures to specific dietary constituents, interactions with the food matrix, processing technologies, or the genomic variation among individuals, which can influence absorption, metabolism, and/or the molecular target. Inter-individual variability in genetics, epigenetics, transcriptomics, proteomics, metabolomics, or microbiomics can influence the magnitude and direction of response to bioactive food components, as briefly reviewed in this article. Unquestionably, understanding nutrigenomics holds promise to reveal those who will benefit most from dietary interventions plus identify any who might be placed at risk due to overexposures.

Small research grants, or R03 grants, provide limited, short-term support for individual research projects. R03s may be an excellent means of support for projects by nutrition scientists at all stages in their careers. The National Cancer Institute (NCI) has awarded roughly one-half of all nutrition-related NIH R03 grants in the period from 2005 to 2010. A detailed review of the recent NCI grant portfolio identified potential strategies for successful applications. Projects that addressed important nutrition and cancer issues had feasible and appropriate specific aims, were innovative, and were based on sound concepts were most positively viewed by reviewers. Furthermore, applicants with suitable expertise, training, mentorship, and records of accomplishment who, when appropriate, collaborated with investigators with complementary knowledge and skills were more likely to receive higher priority scores.

Background: Selenium (Se) status in non-deficient subjects is typically assessed by the Se contents of plasma/serum. That pool comprises two functional, specific selenoprotein components and at least one non-functional, non-specific components which respond differently to changes in Se intake. A more informative means of characterizing Se status in non-deficient individuals is needed., Methods: Multiple biomarkers of Se status (plasma Se, serum selenoprotein P [SEPP1], plasma glutathione peroxidase activity [GPX3], buccal cell Se, urinary Se) were evaluated in relation to selenoprotein genotypes (GPX1, GPX3, SEPP1, SEP15), dietary Se intake, and parameters of single-carbon metabolism in a cohort of healthy, non-Se-deficient men (n = 106) and women (n = 155)., Conclusions: Plasma Se concentration was 142.0 ± 23.5 ng/ml, with GPX3 and serum-derived SEPP1 calculated to comprise 20% and 34%, respectively, of that total. The balance, comprised of non-specific components, accounted for virtually all of the interindividual variation in total plasma Se. Buccal cell Se was associated with age and plasma homocysteine (hCys), but not plasma Se. SEPP1 showed a quadratic relationship with body mass index, peaking at BMI 25-30. Urinary Se was greater in women than men, and was associated with metabolic body weight (kg0.75), plasma folate, vitamin B12 and hCys (negatively). One GPX1 genotype (679T/T) was associated with significantly lower plasma Se levels than other allelic variants. Selenium intake, estimated from food frequency questionnaires, did not predict Se status as indicated by any biomarker. These results show that genotype, methyl-group status and BMI contribute to variation in Se biomarkers in Se-adequate individuals.

A wealth of scientific evidence supports a role for vitamin D in decreasing colorectal cancer incidence, and possibly mortality. This reduction in risk is related to inhibition of cellular proliferation and stimulation of differentiation. The minimal amount and duration needed to bring about these effects necessitate additional studies. Furthermore, a critical evaluation of physiologically relevant biomarkers of vitamin D status, including 25-hydroxyvitamin D, is needed. Several dietary components and the balance between energy intake and expenditure influence vitamin D metabolism. Scientists need to identify confounders and modifiers of the biological response to vitamin D, including dietary factors, lifestyle factors such as exercise, race or ethnicity, and genetic background.

Although there is growing epidemiological, preclinical and clinical evidence suggesting that low vitamin D intake, exposure and/or status is associated with an increased risk of various types of cancer, the optimum amount needed remains controversial. Furthermore, there is evidence that a U- or J-shaped response curve exist between 25(OH)D and certain cancers. Increasing information about the impact of genetic variation, especially polymorphisms that influence absorption, transport, metabolism and associated molecular targets, should help clarify inconsistencies in the data regarding vitamin D's effect on cancer risk. Rather than focusing on the main effects of a few variants of these genes alone, future studies need to consider gene-nutrient or environmental interactions. Nutrigenomics should clarify who might benefit and be placed at risk because of vitamin D exposure., (Copyright © 2011 S. Karger AG, Basel.)

Cancer cells possess unique metabolic signatures compared to normal cells, including shifts in aerobic glycolysis, glutaminolysis, and de novo biosynthesis of macromolecules. Targeting these changes with agents (drugs and dietary components) has been employed as strategies to reduce the complications associated with tumorigenesis. This paper highlights the ability of several food components to suppress tumor-specific metabolic pathways, including increased expression of glucose transporters, oncogenic tyrosine kinase, tumor-specific M2-type pyruvate kinase, and fatty acid synthase, and the detection of such effects using various metabonomic technologies, including liquid chromatography/mass spectrometry (LC/MS) and stable isotope-labeled MS. Stable isotope-mediated tracing technologies offer exciting opportunities for defining specific target(s) for food components. Exposures, especially during the early transition phase from normal to cancer, are critical for the translation of knowledge about food components into effective prevention strategies. Although appropriate dietary exposures needed to alter cellular metabolism remain inconsistent and/or ill-defined, validated metabonomic biomarkers for dietary components hold promise for establishing effective strategies for cancer prevention.

The case for the influence of vitamin D on health, including cancer prevention, is increasingly compelling. While some are calling for increases in the Tolerable Upper Intake Level, fortification, and dietary supplementation, questions regarding dose and individual response variability continue to merit attention. Colorectal cancer risk reduction with adequate vitamin D status is well documented. Protection has also been observed for cancer at all sites, skin, prostate, and breast. At the same time, some individuals may be adversely affected by elevated 25(OH)D concentrations with respect to risk of cancers of the prostate, breast, pancreas, and esophagus, and in some cases a U- or J-shaped association has been suggested. Future research should seek to clarify if and for whom there may be an increased risk for cancer at particular sites with high 25(OH)D concentrations, and the concentrations at which risk increases. Fundamentally, prospective longitudinal studies of these relationships are warranted. The health status, life stage, adiposity, estrogen exposure, and nutritional status of study participants should be taken into account. Continued investigation is necessary to ensure that vitamin D recommendations are appropriately targeted to individuals who stand to benefit most, while protecting vulnerable subgroups from risk of overexposure., (Published by Elsevier Inc.)

Malignant cells are characterized by abnormal signaling pathways involving proliferation, apoptosis, and angiogenesis. These cancer centric pathways are known to be modified by several bioactive dietary components, although admittedly there are inconsistencies in the response. The response is dependent on the amount and duration of exposure to the dietary component and the cell type. While caution should be exercised when extrapolating in vitro data to in vivo conditions, such studies do provide valuable insights into plausible mechanisms. Significant gene-nutrient and nutrient-nutrient interactions may contribute to the uncertainty of the response to foods and/or their components. One of the challenges is the identification of which process(es), either singly or in combination, is/are most important in leading to a dietary-mediated phenotypic change. The dearth of controlled intervention studies that have investigated molecular targets for nutritional preemption in humans make firm dietary recommendations difficult. Until more definite information surfaces, a balanced but varied diet is most prudent., (Published by Elsevier Inc.)

Prostate cancer continues to represent a burgeoning medical problem in the United States. Recent studies suggest that gossypol, a bioactive phytochemical produced by cotton plants, is a promising agent against prostate cancer. The current studies were undertaken to examine the chemotherapeutic efficacy of gossypol on human prostate cancer cell lines and prostate tumor-initiating cells. Gossypol reduced the viability of three prostate cancer cell lines (LAPC4, PC3, and DU145) with an IC(50) between 3 and 5 micromol/L. Additionally, gossypol was effective at inhibiting prostate tumor-initiating cell-driven tumor growth in a nonobese diabetic/severe combined immunodeficient xenograft model. Our integrated molecular profiling approach encompassing proteomics, activated transcription factors, and genomics suggests that the decrease in viability was associated with increased DNA damage and the induction of apoptosis. Exposure of DU145 cells to gossypol (1-10 micromol/L) resulted in the activation of 13 proteins and 7 transcription factors, and the expression of 17 genes involved in the mitochondrial pathway of apoptosis. These studies show for the first time that gossypol treatment induces DNA damage and activates p53. Collectively, these data support the use of gossypol as a novel agent for prostate cancer.

Diet and genetics are both considered important risk determinants for colorectal cancer, a leading cause of death worldwide. Several genetically engineered mouse models have been created, including the ApcMin mouse, to aid in the identification of key cancer related processes and to assist with the characterization of environmental factors, including the diet, which influence risk. Current research using these models provides evidence that several bioactive food components can inhibit genetically predisposed colorectal cancer, while others increase risk. Specifically, calorie restriction or increased exposure to n-3 fatty acids, sulforaphane, chafuroside, curcumin and dibenzoylmethane were reported protective. Total fat, calories and all-trans retinoic acid are associated with an increased risk. Unraveling the importance of specific dietary components in these models is complicated by the basal diet used, the quantity of test components provided and interactions among food components. Newer models are increasingly available to evaluate fundamental cellular processes, including DNA mismatch repair, immune function and inflammation as markers for colon cancer risk. Unfortunately, these models have been used infrequently to examine the influence of specific dietary components. The enhanced use of these models can shed mechanistic insights about the involvement of specific bioactive food and components and energy as determinants of colon cancer risk. However, the use of available mouse models to exactly represent processes important to human gastrointestinal cancers will remain a continued scientific challenge.

Evidence that the intestinal microbiota is intrinsically linked with overall health, including cancer risk, is emerging. Moreover, its composition is not fixed but can be influenced by several dietary components. Dietary modifiers, including the consumption of live bacteria (probiotics) and indigestible or limited digestible food constituents such as oligosaccharides (prebiotics) and polyphenols or both (synbiotics), are recognized modifiers of the numbers and types of microbes and have been reported to reduce colon cancer risk experimentally. Microorganisms also have the ability to generate bioactive compounds from food components. Examples include equol from isoflavones, enterodiol and enterolactone from lignans and urolithins from ellagic acid, which have also been demonstrated to retard experimentally induced cancers. The gastrointestinal microbiota can also influence both sides of the energy balance equation, namely, as a factor influencing energy utilization from the diet and as a factor that influences host genes that regulate energy expenditure and storage. Because of the link between obesity and cancer incidence and mortality, this complex complexion deserves greater attention. Overall, a dynamic interrelationship exists between the intestinal microbiota and colon cancer risk, which can be modified by dietary components and eating behaviors.

Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1 (XBP1), and p53. In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment., ((c) 2009 Wiley-Liss, Inc.)

Various dietary components may modify chronic inflammatory processes at the stage of cytokine production, amplification of nuclear factor-kappaB-mediated inflammatory gene expression, and the release of anti-inflammatory cytokine, transforming growth factor-beta. This review provides a synopsis of the strengths and weaknesses of the evidence that specific bioactive food components influence inflammation-related targets linked to cancer. A target repeatedly surfacing as a site of action for several dietary components is transforming growth factor beta. Whereas the use of dietary intervention strategies offers intriguing possibilities for maintaining normal cell function by modifying a process that is essential for cancer development and progression, more information is needed to characterize the minimum quantity of the bioactive food components required to bring about a change in inflammation-mediated cancer, the ideal time for intervention, and the importance of genetics in determining the response. Unquestionably, the societal benefits of using foods and their components to prevent chronic inflammation and associated complications, including cancer, are enormous.

We examine how a public health genomics framework can be used to move genomic discoveries into clinical and public health practice for obesity prevention and treatment. There are four phases of translational research: T1: discovery to candidate health application; T2: health application to evidence-based practice guidelines; T3: practice guidelines to health practice; and T4: practice to population health impact. Types of multidisciplinary research and knowledge synthesis needed for each phase, as well as the importance of developing and disseminating evidence-based guidelines, are discussed. Because obesity genomics research is mostly in the discovery phase or in the very early phases of translation (T1), the authors present this framework to illustrate the range of translation activities needed to move genomic discoveries in obesity to actual applications that reduce the burden of obesity at the population level.

Personalizing nutrition for cancer prevention and therapy will require a comprehensive understanding of "genotypes/phenotypes" in order to identify, evaluate, and prioritize appropriate points for dietary intervention. This nutritional preemption roadmap must begin with accurately assessing intakes/exposures of which bioactive food component(s) is needed to bring about a desired response in critical cellular processes (carcinogen metabolism, DNA repair, cell proliferation, apoptosis, inflammation, immunity, differentiation, angiogenesis, hormonal regulation and cellular energetic) within an individual. Understanding this "individuality" through a better understanding of the "omics" is fundamental to arriving at the correct destination and thus interpreting biological variables which establish the magnitude or direction of a response to bioactive food components.

Historically, herbs and spices have enjoyed a rich tradition of use for their flavor enhancement characteristics and for their medicinal properties. The rising prevalence of chronic diseases worldwide and the corresponding rise in health care costs is propelling interest among researchers and the public for multiple health benefits related to these food items, including a reduction in cancer risk and modification of tumor behavior. A growing body of epidemiological and preclinical evidence points to culinary herbs and spices as minor dietary constituents with multiple anticancer characteristics. This review focuses on the antimicrobial, antioxidant, and antitumorigenic properties of herbs and spices; their ability to influence carcinogen bioactivation; and likely anticancer contributions. While culinary herbs and spices present intriguing possibilities for health promotion, more complete information is needed about the actual exposures to dietary components that are needed to bring about a response and the molecular target(s) for specific herbs and spices. Only after this information is obtained will it be possible to define appropriate intervention strategies to achieve maximum benefits from herbs and spices without eliciting ill consequences.

Metabolomics is the systematic study of small-molecular-weight substances in cells, tissues and/or whole organisms as influenced by multiple factors including genetics, diet, lifestyle and pharmaceutical interventions. These substances may directly or indirectly interact with molecular targets and thereby influence the risk and complications associated with various diseases, including cancer. Since the interaction between metabolites and specific targets is dynamic, knowledge regarding genetics, susceptibility factors, timing, and degree of exposure to an agent (drug or food component) is fundamental to understanding the metabolome and its potential use for predicting and preventing early phenotypic changes. The future of metabolomics rests with its ability to monitor subtle changes in the metabolome that occur prior to the detection of a gross phenotypic change reflecting disease. The integrated analysis of metabolomics and other 'omics' may provide more sensitive ways to detect changes related to disease and discover novel biomarkers. Knowledge regarding these multivariant characteristics is critical for establishing validated and predictive metabolomic models for cancer prevention. Understanding the metabolome will not only provide insights into the critical sites of regulation in health promotion, but will also assist in identifying intermediate or surrogate cancer biomarkers for establishing preemptive/preventative or therapeutic approaches for health. While unraveling the metabolome will not be simple, the societal implications are enormous.